Beyond Glucocorticoids: The Current Landscape and Prospects for Treating Immune Checkpoint Inhibitor-Induced Autoimmunity.

Abstract

The rapid integration of immune checkpoint inhibitors (ICIs) into standard oncology protocols has birthed a new frontier in clinical rheumatology: immune-related adverse events (irAEs). By disrupting the programmed cell death-1 (PD-1)/PD-L1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) axes to restore antitumor T cell activity, these therapies inadvertently breach peripheral tolerance. This results in a spectrum of de novo autoimmune and inflammatory syndromes that frequently mimic established rheumatic diseases, including inflammatory arthritis and myositis. Although ICIs have revolutionized survival outcomes, the resultant irAEs pose a significant clinical challenge, affecting nearly 50% of patients and often necessitating the expertise of rheumatologists for management. This manuscript explores the unique rheumatologic phenotype of ICI-induced toxicities, emphasizing the urgent need for a shift from broad-spectrum glucocorticoid use toward targeted, mechanism-driven therapies that do not compromise the abscopal antitumor effect. We review the current landscape of clinical trials investigating the repurposing of traditional disease-modifying antirheumatic drugs and advanced biologics. Specifically, we discuss the efficacy and safety of tumor necrosis factor-alpha inhibitors, interleukin-6 receptor antagonists, and JAK inhibitors in the context of steroid-refractory irAEs. We further analyze the molecular commonalities between idiopathic autoimmune diseases and ICI-induced inflammation. As the patient population receiving ICIs grows, the rheumatologist's role as a co-manager is increasingly essential. This review highlights the need for standardized grading and treatment algorithms for rheumatologic irAEs and advocates collaborative research to separate immunotherapy toxicities from its oncological benefits.